The ultimate goals of these investigations are to delineate the cellular mechanisms of cardiac preconditioning. Experimental transient ischemia and clinical angina both promote myocardial viability and mechanical function in response to sustained ischemia/reperfusion. Predictably, therapeutic utilization of myocardial ischemia as a protective "preconditioning" stimulus has proven anathema to cardiologists/surgeons. Several hormones and pharmacologic agents have surfaced that appear to reproduce cardiac protection against a sustained ischemic insult. All of the several hundred thousand cardiac surgical procedures performed each year rely upon cold hyperkalemic myocardial preservation techniques. Lack of mechanistic familiarity with cardiac "preconditioning" has delayed incorporation of this physiologic phenomenon into current therapy.Cardiac ischemia induces myocyte acidosis that can be attenuated by: 1) reduced metabolic proton production, 2) intracellular buffering and 3) membrane proton exchange. Proton pump extrusion may mandate membrane sodium exchange which in sequence may be bumped out of the cell in return for an increase in intracellular calcium. Both the intracellular hypernatremia and hypercalcemia could provoke both diastolic and systolic myocellular dysfunction. Ischemic/hormonal/pharmacologic "cardiac preconditioning" has been associated with a translocation (activation) of multiple isomers of protein kinase C. The proposed series of studies will clarify the putative link between clinically attractive hormone/pharmacologic agents, specific PKC isomers and mechanisms of antiacidosis during cardiac preconditioning and subsequent sustained cardiac ischemia/reperfusion. The potential application of these observations initially to all scheduled cardiac surgical procedures and ultimately to both percutaneous angioplasty and subsequently the medical therapy of myocardial ischemia should be substantial.